PMID- 34135912 OWN - NLM STAT- MEDLINE DCOM- 20211027 LR - 20211027 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Preservation of Gastrointestinal Mucosal Barrier Function and Microbiome in Patients With Controlled HIV Infection. PG - 688886 LID - 10.3389/fimmu.2021.688886 [doi] LID - 688886 AB - BACKGROUND: Despite successful ART in people living with HIV infection (PLHIV) they experience increased morbidity and mortality compared with HIV-negative controls. A dominant paradigm is that gut-associated lymphatic tissue (GALT) destruction at the time of primary HIV infection leads to loss of gut integrity, pathological microbial translocation across the compromised gastrointestinal barrier and, consequently, systemic inflammation. We aimed to identify and measure specific changes in the gastrointestinal barrier that might allow bacterial translocation, and their persistence despite initiation of antiretroviral therapy (ART). METHOD: We conducted a cross-sectional study of the gastrointestinal (GIT) barrier in PLHIV and HIV-uninfected controls (HUC). The GIT barrier was assessed as follows: in vivo mucosal imaging using confocal endomicroscopy (CEM); the immunophenotype of GIT and circulating lymphocytes; the gut microbiome; and plasma inflammation markers Tumour Necrosis Factor-alpha (TNF-alpha) and Interleukin-6 (IL-6); and the microbial translocation marker sCD14. RESULTS: A cohort of PLHIV who initiated ART early, during primary HIV infection (PHI), n=5), and late (chronic HIV infection (CHI), n=7) infection were evaluated for the differential effects of the stage of ART initiation on the GIT barrier compared with HUC (n=6). We observed a significant decrease in the CD4 T-cell count of CHI patients in the left colon (p=0.03) and a trend to a decrease in the terminal ileum (p=0.13). We did not find evidence of increased epithelial permeability by CEM. No significant differences were found in microbial translocation or inflammatory markers in plasma. In gut biopsies, CD8 T-cells, including resident intraepithelial CD103+ cells, did not show any significant elevation of activation in PLHIV, compared to HUC. The majority of residual circulating activated CD38+HLA-DR+ CD8 T-cells did not exhibit gut-homing integrins alpha4ss7, suggesting that they did not originate in GALT. A significant reduction in the evenness of species distribution in the microbiome of CHI subjects (p=0.016) was observed, with significantly higher relative abundance of the genus Spirochaeta in PHI subjects (p=0.042). CONCLUSION: These data suggest that substantial, non-specific increases in epithelial permeability may not be the most important mechanism of HIV-associated immune activation in well-controlled HIV-positive patients on antiretroviral therapy. Changes in gut microbiota warrant further study. CI - Copyright (c) 2021 Mak, Zaunders, Bailey, Seddiki, Rogers, Leong, Phan, Kelleher, Koelsch, Boyd and Danta. FAU - Mak, Gerald AU - Mak G AD - St. Vincent's Clinical School, UNSW, Darlinghurst, NSW, Australia. FAU - Zaunders, John J AU - Zaunders JJ AD - Centre for Applied Medical Research, St Vincent's Hospital, Sydney, NSW, Australia. FAU - Bailey, Michelle AU - Bailey M AD - Kirby Institute, UNSW Sydney, Sydney, NSW, Australia. FAU - Seddiki, Nabila AU - Seddiki N AD - IDMIT Department/IBFJ, Immunology of Viral Infections and Autoimmune Diseases (IMVA), INSERM U1184, CEA, Universite Paris Sud, Paris, France. FAU - Rogers, Geraint AU - Rogers G AD - South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia. AD - Faculty of Science, Flinders University, Adelaide, SA, Australia. FAU - Leong, Lex AU - Leong L AD - Microbiology and Infectious Diseases, South Australia (SA) Pathology, Adelaide, SA, Australia. FAU - Phan, Tri Giang AU - Phan TG AD - St. Vincent's Clinical School, UNSW, Darlinghurst, NSW, Australia. AD - Immunology Division Garvan Institute of Medical Research, Sydney, NSW, Australia. FAU - Kelleher, Anthony D AU - Kelleher AD AD - Kirby Institute, UNSW Sydney, Sydney, NSW, Australia. FAU - Koelsch, Kersten K AU - Koelsch KK AD - Kirby Institute, UNSW Sydney, Sydney, NSW, Australia. FAU - Boyd, Mark A AU - Boyd MA AD - Kirby Institute, UNSW Sydney, Sydney, NSW, Australia. AD - South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia. AD - Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia. FAU - Danta, Mark AU - Danta M AD - St. Vincent's Clinical School, UNSW, Darlinghurst, NSW, Australia. AD - Department of Gastroenterology, St. Vincent's Hospital, Sydney, NSW, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210531 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Anti-HIV Agents) RN - 0 (Biomarkers) RN - 0 (CD14 protein, human) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (TNF protein, human) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Adult MH - Anti-HIV Agents/*therapeutic use MH - *Bacterial Translocation MH - Biomarkers/blood MH - CD4-Positive T-Lymphocytes/immunology/metabolism MH - CD8-Positive T-Lymphocytes/immunology/metabolism MH - Case-Control Studies MH - Cross-Sectional Studies MH - *Gastrointestinal Microbiome MH - HIV Infections/*drug therapy/immunology/virology MH - *HIV Long-Term Survivors MH - Humans MH - Immunity, Mucosal MH - Interleukin-6/blood MH - Intestinal Mucosa/immunology/*microbiology/pathology MH - Lipopolysaccharide Receptors/blood MH - Lymphoid Tissue/immunology/metabolism MH - Male MH - Middle Aged MH - Permeability MH - Pilot Projects MH - Treatment Outcome MH - Tumor Necrosis Factor-alpha/blood PMC - PMC8203413 OTO - NOTNLM OT - CD4 OT - HIV OT - antiretroviral therapy (ART) OT - gut-associated lymphoid tissues (GALT) OT - microbiome COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor has declared a shared affiliation, though no other collaboration with one of the authors NS at the time of review. EDAT- 2021/06/18 06:00 MHDA- 2021/10/28 06:00 PMCR- 2021/01/01 CRDT- 2021/06/17 06:41 PHST- 2021/03/31 00:00 [received] PHST- 2021/05/04 00:00 [accepted] PHST- 2021/06/17 06:41 [entrez] PHST- 2021/06/18 06:00 [pubmed] PHST- 2021/10/28 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.688886 [doi] PST - epublish SO - Front Immunol. 2021 May 31;12:688886. doi: 10.3389/fimmu.2021.688886. eCollection 2021.